Metering system and method for aerosol delivery

ABSTRACT

A method for metering the delivery of a fluid. The apparatus has a variable acoustic source and a microphone, both acoustically coupled to a volume having a fluid region and an air region. The apparatus may also include a processor to determine a volume of the air region based on signals received from the microphone and the variable acoustic source. A fluid valve is coupled to the processor, and is configured to allow an amount of fluid to exit the fluid region associated with the volume of the air region.

RELATED APPLICATIONS

The present application is a Continuation of U.S. patent applicationSer. No. 13/968,710, filed Aug. 16, 2013 and entitled “Metering Systemand Methods for Aerosol Delivery”, which is a Continuation ofApplication of U.S. patent application Ser. No. 12/897,100, filed Oct.4, 2010 and entitled “Metering System and Method for Aerosol Delivery”,now U.S. Pat. No. 8,511,299, issued Aug. 20, 2013, which is aContinuation Application of U.S. patent application Ser. No. 11/942,883,filed Nov. 20, 2007 and entitled “Method System and Method for AerosolDelivery”, now U.S. Pat. No. 7,806,116, issued Oct. 5, 2010, which is aContinuation of U.S. patent application Ser. No. 10/670,641, filed Sep.25, 2003 and entitled “Metering System and Method for Aerosol Delivery”,now U.S. Pat. No. 7,305,984, issued Dec. 11, 2007, all of which arehereby incorporated herein by reference in their entireties.

Additionally, the present application contains subject matter related tothat of U.S. patent application Ser. No. 10/675,278, filed Sep. 30, 2003and entitled “Detection System and Method for Aerosol Delivery”, nowU.S. Pat. No. 7,342,660, issued Mar. 11, 2008; U.S. patent applicationSer. No. 10/670,977, filed Sep. 25, 2003 and entitled “System and Methodfor Improved Volume Measurement,” now U.S. Pat. No. 7,066,029, issuedJun. 27, 2006; U.S. patent application Ser. No. 10/671,278, filed Sep.25, 2003 and entitled “System and Method for Aerosol Delivery,” now U.S.Pat. No. 7,021,560, issued Apr. 4, 2006; and U.S. patent applicationSer. No. 10/670,924, filed Sep. 25, 2003 and entitled “Valve System andMethod for Aerosol Drug Delivery,” now U.S. Pat. No. 7,146,977, issuedDec. 12, 2006. The disclosures of the foregoing are incorporated hereinby reference.

FIELD OF THE INVENTION

The present invention generally relates to systems and methods formetering and outputting quantities of aerosolized substances. Moreparticularly, embodiments of the present invention can relate to systemsand methods for accurately delivering atomized drugs.

BACKGROUND

Aerosolized drugs for inhalation are considered reasonable alternativesto injections or other types of drug-delivery systems, such asintravenous delivery, subcutaneous injection, and intra-muscular. Forexample, insulin can be delivered by inhaling an aerosolized form, thussparing a patient pain and inconvenience caused by subcutaneousinjection of insulin.

Inhaling aerosols, however, typically lacks the accuracy of injections,and so is inappropriate for use in situations where accurate dosing iscritical. With aerosolized drugs, the proper amount required fordelivery is often not properly metered for delivery. For example, asthmainhalers typically have an acceptable accuracy of plus or minus 25% ofthe nominal dose. For systemic drug delivery of insulin, on the otherhand, such a level of accuracy is considered too unpredictable to allowfor appropriate use, even though aerosolized delivery is much lessharmful to a patient than intravenous delivery.

Thus, a need exists for accurately and predictably delivering apredetermined dose of aerosolized drugs.

SUMMARY OF THE INVENTION

An embodiment comprises a variable acoustic source and a microphone,both acoustically coupled to a volume that is divided into an air regionand a fluid region. A processor is configured to receive a signal fromthe microphone, and to determine a volume of the air region. A fluidvalve is configured to allow an amount of fluid to exit the fluidregion, the amount of fluid being associated with the volume of the airregion. An atomizer is coupled to the fluid region, and is configured toaerosolize at least a portion of the amount of fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a system for outputting an aerosol,according to an embodiment of the invention.

FIG. 2 is a schematic diagram of a system for outputting an aerosol,according to an embodiment of the invention in the context ofaerosolized drug delivery.

FIG. 3 is a schematic diagram of acoustic volume sensors that can beused with three embodiments of the invention.

FIG. 4 is a schematic diagram of an acoustic volume sensor according toan embodiment of the invention.

FIGS. 5A-5C is a schematic diagram of a number of acoustic volumesensors that further describe and explain embodiments of the invention.

FIG. 6 is a schematic diagram of a mechanical analog to the systemaccording to an embodiment of the invention.

FIG. 7 is a cutaway view of a detachable cassette for which a volumedetermination can be made, according to an embodiment of the invention.

FIG. 8 is a top view of a detachable cassette for which a volumedetermination can be made, according to an embodiment of the invention.

FIG. 9 is a schematic diagram of a signal processing technique accordingto an embodiment of the invention.

FIG. 10 is a flow chart of the signal processing technique illustratedin FIG. 9.

FIG. 11 is a schematic diagram of a signal processing techniqueaccording to an embodiment of the invention.

FIG. 12 is a flow chart of the signal processing technique illustratedin FIG. 11.

FIG. 13 is a schematic diagram of a signal processing technique using aspeaker impulse, according to an embodiment of the invention.

FIG. 14 is a flow chart of the signal processing technique illustratedin FIG. 13.

FIG. 15 is a schematic diagram of an embodiment of the invention thatdoes not require the presence of an acoustic port.

FIG. 16 is a schematic diagram of a low-frequency approximation of anacoustic volume sensor, according to an embodiment of the invention.

FIG. 17 is a schematic diagram of a high-frequency approximation of anacoustic volume sensor, according to an embodiment of the invention.

FIG. 18 is a flow chart of a signal processing technique using amplituderatio measurements, according to an embodiment of the invention.

DETAILED DESCRIPTION

Embodiments of the invention include systems and methods for outputtingan aerosol. For purposes of this application, the term aerosol includesairflows containing particles, such as aerosolized liquids, powders, andcombinations of the two. FIG. 1 displays a schematic overview of asystem for outputting an aerosol, according to an embodiment of theinvention. In this embodiment, variable acoustic source 101 andmicrophone 102 are acoustically coupled to chamber 103. Volume 103 isdivided into air region 103 a and fluid region 103 b. For purposes ofthis application, the term air includes any gas or combination of gases.

Processor 104 is configured to receive a signal from microphone 102, andto determine a volume of air region 103 a. Processor 104 is incommunication with fluid valve 105, and is configured to send a controlsignal to fluid valve 105 to open and close fluid valve 105 to allow anamount of fluid out from fluid region 103 b into target region 106. Theamount of fluid released into target region 106 is associated with thedetermined volume of air region 103 a. In one embodiment, chamber 103 isa fixed volume, and so the volume of fluid released into target region106 is substantially identical to a determined change in volume of airregion 103 a. Target region 106 is coupled to atomizer 107, which isconfigured to aerosolize at least a portion of the fluid that has exitedfluid region 103 b.

In one embodiment, the system includes a second processor 119 that isconfigured to calculate a volume of the aerosolized fluid, and isfurther configured to output a volume signal associated with thecalculated volume. In this embodiment, the amount of fluid allowed toenter target region 106 is associated both with the volume of air region103 a and with the aerosol volume.

The second processor is configured to receive a signal from volumesensor 108 in communication with aerosol flow chamber 111. Volume sensor108 can be any combination of hardware and software configured tocollect information for determining aerosol volume. For the purposes ofthe invention, the terms pressure, air flow and flow rate are all usedinterchangeably, depending on the context.

The second processor is not shown in FIG. 1, and for the purposes of theinvention, processor 104 and the second processor can be the sameprocessor, or can be separate from each other. For the purposes of theinvention, the term processor includes, for example, any combination ofhardware, computer programs, software, firmware and digital logicalprocessors capable of processing input, executing algorithms, andgenerating output as necessary to practice embodiments of the presentinvention. The term processor can include any combination of suchprocessors, and may include a microprocessor, an Application SpecificIntegrated Circuit (ASIC), and state machines. Such a processor caninclude, or can be in communication with, a processor readable mediumthat stores instructions that, when executed by the processor, causesthe processor to perform the steps described herein as carried out, orassisted, by a processor.

For the purposes of the invention, “processor readable medium,” orsimply “medium,” includes but is not limited to, electronic, optical,magnetic, or other storage or transmission devices capable of providinga processor with processor readable instructions. Other examples ofsuitable media include, but are not limited to, a floppy disk, CD-ROM,magnetic disk, memory chip, ROM, RAM, ASIC, configured processor, alloptical media, all magnetic tape or other magnetic media, or any othermedium from which a processor can read. Also, various other forms ofprocessor readable media may transmit or carry instructions to acomputer, including a router, private or public network, or othertransmission device or channel. Also, various other forms of processorreadable media may transmit or carry instructions to a computer,including a router, private or public network, or other transmissiondevice or channel.

Target region 106 is coupled to air valve 109 and air source 110.Processor 104 can be further configured to send a control signal to airvalve 109 to open and close air valve 109, thereby selectively exposingair source 110 to target region 106 and to atomizer 107. Air source 110can be a compressed air source or liquefied air source, an air sourceopen to the atmosphere, or any air source useful for moving fluid fromtarget region 106 to atomizer 107, and/or for purging target region 106.In one alternative embodiment, air source 110 may comprise a volumecontaining an amount of liquefied propellant gas, where air valve 109 isconfigured in such a way as to connect to the portion of the volumetypically containing vapor.

In one preferred embodiment, air source 110 is connected to targetregion 106 through air valve 109 in close proximity to fluid valve 105.Thus, when air valve 109 is opened, air from air source 110 will push asubstantial portion of the volume of fluid in target region 106 towardthe physical gap 112 in closed volume 113 and then to atomizer 107.Additionally, if the internal diameter of target region 106 iscomparatively narrow, such as in a small bore capillary, utilizing airfrom air source 110 to push the volume of fluid in target region 106toward atomizer 107 may have the additional advantages of reducing oreliminating blockage of the system, such as crystal growth, andbiological contamination that could result from fluid remainingotherwise remain in target region 106 and improving accuracy of thesystem by ensuring that a substantial portion of the fluid exits targetregion 106 toward atomizer 107.

FIG. 2 is a schematic diagram of a system for outputting an aerosol,according to an embodiment of the invention, in the context ofaerosolized drug delivery. In this embodiment, acoustic volume sensor201 is coupled to disposable drug cassette 202. Pressure source 203 iscoupled to acoustic volume sensor 201 to assist in outputting the drugfrom acoustic volume sensor 201 to disposable cassette 202. Disposablecassette 202 includes drug reservoir 202 a, valve 202 b and atomizer 202c, and is detachably coupled to acoustic volume sensor 201. Atomizer 202c can be, for example, an electro-hydrodynamic atomizer. Processor 204is coupled to acoustic volume sensor 201 to calculate an amount of drugto output from drug reservoir 202 a, and to control valve 202 b.

Atomizer 202 c is coupled to air flow sensor system 205. Air flow sensorsystem 205 can be any known system for measuring air flow or pressure ofthe aerosolized drug to be output to a patient. For example, air flowsensor system 205 can include an anemometer, a pin-wheel sensor, or anyother sensor operable to measure air flow, flow rate or pressure. In theembodiment shown, air flow sensor system 205 is a light scatterdetection system that includes light source 205 a, light detector 205 b,and pressure sensor 205 c. Processor 204 is coupled to light source 205a, light detector 205 b and pressure sensor 205 c. Processor 204 isconfigured to receive a light detection signal 205 b and pressure or airflow signal from pressure sensor 205 c, and calculate the aerosol volumeinside air flow sensor system 205. As stated above, this system isdescribed in detail in U.S. patent application Ser. No. 10/670,655,titled “Detection System and Method for Aerosol Delivery.”

Processor 204 is further coupled to power 206 to power the atomizer onand off at the appropriate time. FIG. 3 is a schematic diagram ofacoustic volume sensors that can be used with three embodiments of theinvention. In each embodiment, the chamber has volume V1, and isacoustically coupled to port M1 to form an acoustic system. Microphone301 (or other suitable acousto-electrical transducer) and an acousticsource 302, such as a speaker, (or other suitable electro-acousticaltransducer) are acoustically coupled to this acoustic system. Theelectrical output of the microphone is placed in communication withelectrical input of acoustic source 302, in such a way that theamplitude and phase relationships of the signals promote acousticresonance of the system. A measurement of a quantity related to thesystem's resonant frequency can permit determination of the chambervolume, as is described in U.S. Pat. No. 5,349,852, incorporated hereinin its entirety. Such a resonance frequency measurement can be achievedin a processor. Alternatively, an additional chamber of known volume,configured with a port in a manner similar to one of the embodiments ofFIG. 3, may be employed to produce a resonance, and a quantity relatedto the resonant frequency may be measured. This can, in turn, lead to adetermination of the relevant volume.

In embodiment (1) of FIG. 3, microphone 301 is placed within thechamber, and acoustic source 302 forms a portion of the wall of thechamber. Because the resonance determination does not require that thechamber be sealed in the fashion required for acoustic-pressure typesystems, the transducers employed in these embodiments do not need to belocated in the chamber forming part of the system. It is necessary onlythat the transducers be acoustically coupled to the system.

In embodiments (2) and (3) of FIG. 3, a second volume V2 is associatedwith the system and is coupled to volume V1 via port M1. In each ofembodiments (2) and (3), acoustic source 302 forms a portion of the wallof volume V2, and can be, for example, a piezoelectric speaker. Inembodiment (2), microphone 301, which can be, for example, of thevelocity type, forms a part of the wall between volumes V1 and V2, andresponds only to differences in pressure between the two volumes;because the pressure difference between the two volumes tends to be nearzero at frequencies below the frequency of natural resonance of thesystem, noise in microphone 301 is effectively canceled out. Inembodiment (3), microphone 301 is disposed in volume V2.

FIG. 4 is a schematic diagram of an acoustic volume sensor according toan embodiment of the invention. In this embodiment, acoustic volumesensor enclosure 400 includes first volume 401 and second volume 402,separated by printed circuit board 403. First microphone 404 isacoustically coupled to first volume 401, and second microphone 405 isacoustically coupled to second volume 402.

Printed circuit board 403 contains an acoustic source, which can be, forexample, a piezoelectric speaker. In one embodiment, one or both offirst microphone 404 and second microphone 405 is attached to printedcircuit board 403. Printed circuit board 403 can include, in oneembodiment, an inner layer configured to pass electrical signals.Printed circuit board 403 is coupled to acoustic volume sensor enclosure400 in a way that forms a substantially air-tight seal. In oneembodiment, printed circuit board 403 includes a hole to equalizepressure between the first volume and the second volume. In thisembodiment, the hole is small enough so as to not adversely impact theacoustic qualities of the system.

First microphone 404 and second microphone 405 are coupled to aprocessor (not shown). This processor is configured to receive a signalfrom the microphones, and is further configured to determine a volume ofthe variable-volume chamber based on the received signals. In oneembodiment, the processor is contained on printed circuit board 403.

Second volume 402 is coupled to third volume 407 via port 408 in such away as to create an acoustic system including second microphone 405 andacoustic source 406. Third volume 407 is divided into air portion 407 aand fluid portion 407 b. In one embodiment, third volume 407 is adetachable cassette. Air portion 407 a can contain air, or can containany suitable gas for creating an acoustic resonance for volumedetermination. Fluid portion 407 b can include any fluid, includingmedicine, ink, or any fluid for which a volume measurement is desired.In one embodiment, air portion 407 a is separated from fluid portion 407b by a diaphragm 409. Diaphragm 409 is configured to allow for a volumemeasurement of air portion 407 a. Fluid portion 407 b of third volume407 includes fluid output fitting 410 for allowing fluid to escape fromfluid volume 407 b in a controlled way.

The basic theory behind the acoustic volume sensor according to anembodiment of the invention is that two chambers of air separated by arelatively small tube of air will resonate at a specific frequency whenprovided with an impulse to either of the air chambers or to the air inthe tube that connects the chambers. The resultant resonant frequency isrelated to the volumes of the chambers, the tube dimensions andmiscellaneous parameters of the gas that is used as a medium within theresonator.

To ensure a resonance exists as described by the basic theory, someassumptions may be used. First, the wavelength associated with theresonant frequency should be significantly larger than any of thecritical dimensions of the resonator. Typically, the free-spacewavelength associated with an acoustic wave of the resonant frequencyshould be approximately 20 times larger than the diameter of thechambers, and also of the length and diameter of the tube. Thisassumption provides that the air pressure within a given chamber isapproximately uniform throughout the volume and that the air in the tubeis also at a uniform pressure. Resonators having resonant frequencieswith wavelengths less than 20 times the critical dimensions can bedesigned with acceptable behavior. The applicability of the assumptions,however, and the relevance of the theory will be diminished as thewavelength is decreased (or, conversely, the resonant frequency isincreased) for a given resonator design.

Second, the energy lost from the resonator should be kept small so thatthe resonator will be underdamped. The resonator is modeled as asecond-order system and the corresponding losses (damping) should bekept small so that the resonance can be readily observed. No widelyaccepted “rules of thumb” exist to determine the acceptability ofvarious losses. Furthermore, no extensive studies have been performed todetermine, without experimentation, the degree of losses that areexpected for a given resonator geometry. Most of the losses are believedto be the result of viscous losses to the walls of the tube as the airtraverses the tube's length.

Finally, at all frequencies of interest, the acoustic processes shouldbe adiabatic. In other words, the acoustic processes should occur at arate sufficient to keep heat energy from either leaving the system orequilibrating with the surrounding media. For the purposes of thisdocument, acoustic processes at audible frequencies are alwaysconsidered to be adiabatic.

FIGS. 5A-5C is a schematic diagram of a number of acoustic volumesensors that further describe and explain embodiments of the invention.All of the following representations are considered equivalent with theonly differences being required for practical implementation. FIG. 5adescribes a simplified resonator using a piston 501 a to vary the V₁volume and excite the system. FIG. 5b replaces the piston with a speaker501 b for excitation and incorporates microphones 502 b and 503 b fordetermining the acoustic pressure levels present in the V₀ and V₁volumes.

FIG. 5c depicts the implementation details required to utilize theresonator for measurement of volumes that vary as a result of fluidmovements using a diaphragm as an interface and valves for control. Inthis figure, speaker 501 c is used to excite the system, and microphones502 c and 503 c for determining the acoustic pressure levels present inthe V₀ and V₁ volumes.

Volume V₂ is acoustically coupled to volume V₁ via port 504 c. Volume V₂can be detachable from volume V₁ at port 504 c. Volume V₂ includes gasregion 505 c and fluid region 506 c. In one embodiment, fluid region 506c can be bounded by delivery input valve 508 c and patient valve 509 c.Delivery input valve 508 c is configured to be coupled to a fluid sourcethat allows fluid to flow into the volume for metering upon output.Patient valve 509 c can be processor controlled to open and close toallow a specific volume of fluid to exit fluid region 506 c.

The theoretical acoustic behavior can be modeled using a simplemechanical analog. Air volumes have frequency-dependent performanceanalogous to springs. Air ports have frequency-dependent performanceanalogous to masses. Acoustic dampers within air ports have an analogouseffect on performance as a frictional surface over which a mass isforced to slide.

FIG. 6 is a schematic diagram of a mechanical analog of an acousticvolume sensor according to an embodiment of the invention. In FIG. 6, tomake the analogy explicit, spring 601 has a spring constant K₀ analogousto the volume V₀, spring 602 has a spring constant K₁ analogous tovolume V₁, and spring 607 has a spring constant K₂ analogous to volumeV₂. Reference force sensor 603 is analogous to the reference microphone,and front force sensor 604 is analogous to the front microphone. Piston605 can excite the system in a way analogous to the speaker, drivingmass 606 analogously to the air port.

Similarly, embodiments of the acoustic volume sensor can be modeled asan electrical circuit (not shown), with capacitors taking the place ofsprings (or volumes), a current source driving the system in place ofthe piston (or speaker), and inductors and resistors representing themass (or port).

FIG. 7 is a cutaway view of a detachable cassette for which a volumedetermination can be made, according to an embodiment of the invention.In this embodiment, housing 701 contains selectable volume 702, which isdivided into air chamber 703 and fluid chamber 704. Air chamber 703 andfluid chamber 704 are, in one embodiment, separated by a diaphragm.

Housing 701 includes air port 705 for coupling to an air source such asa condensed air source. Housing 701 further includes AVS port 706 foracoustically coupling volume 702 to an acoustic volume sensor.

In one embodiment, housing 701 can contain multiple selectable volumes702, each with a corresponding AVS port 706, air port 705, valve 707 andfluid/air path 708. In one embodiment, one selectable volume 702 canshare an AVS port 706, an air port 705, a valve 707 and a fluid/air path708 with another selectable volume 702. Each selectable volume 702 isconfigured to be individually selectable for acoustic coupling with anacoustic volume sensor.

In one embodiment, fluid chamber 704 is coupled to valve 707 byfluid/air path 708 for outputting a selected amount of fluid from fluidchamber 704, based on a volume determined in air chamber 703. Fluid/airpath 708 is further configured to be coupled to an air source forpurging parts of the system.

In one embodiment, valve 707 is configured to be coupled to fluidchamber 704 when fluid chamber 704 is coupled to an acoustic volumesensor. Valve 707 is further configured to be coupled to a processor(not shown), and configured to receive a control signal from theprocessor to open and close based on a volume determined in air chamber703. Valve 707 is configured to be coupled to an atomizer.

FIG. 8 is a top view of a detachable cassette for which a volumedetermination can be made, according to an embodiment of the invention.In this embodiment, the detachable cassette includes 7 selectablevolumes, which can be seen from the corresponding air ports 805 andacoustic volume sensor ports 806. In principle, housing 801 can includeany practicable number of selectable volumes.

Valve 807 can be seen attached to acoustic volume sensor coupling 809.Acoustic volume sensor coupling 809 is configured to detachably couplethe detachable cassette to a fluid volume sensor in a way that allowsany selectable volume to be selectably coupled to an acoustic volumesensor.

Acoustic volume sensors can employ a number of signal processingtechniques to determine the resonance and volume of a variable volumechamber. FIGS. 9-23 illustrate several exemplary methods of signalprocessing. In FIG. 9, a speaker is driven with a fixed frequencysinusoid and the phase difference between microphones 901 and 902 ismeasured. In this embodiment, the microphone outputs are passed throughzero-crossing detector 903 to create digital square waves in phase withtheir analog sine outputs. The two square waves are then passed throughan exclusive OR gate, XOR 904; the duty cycle of the XOR 904 output,which is proportional to the phase difference, is measured. Afterdetermining the phase difference, a different frequency is output fromspeaker 905, and the new phase difference is measured. This is repeateduntil the system finds the frequencies for which the phase differencestraddles 90 degrees. Linear interpolation can then be used to calculatethe system's resonant frequency. Phase difference is measured, and thesystem is controlled, by processor 906.

FIG. 10 is a flow chart describing the steps of acoustic volume sensingusing the digital duty-cycle technique illustrated in FIG. 9. In oneembodiment, at step 1001, a duty-cycle counter is configured, andtransmission to a speaker is initiated. The speaker is configured inthis embodiment to output a fixed frequency sinusoidal signal.

At step 1002, counter data is accumulated as the speaker transmission iscompleted. The phase difference between the two microphones, at step1003, is then calculated using the duty cycle of the XOR output usingthe equation phase (in degrees)=180*duty cycle(0-1).

Once the phase difference is determined, then at step 1004, adetermination is made as to whether the phase difference is within somepredetermined window of 90 degrees. If not, then at step 1005, the drivefrequency is changed to move the phase measurement closer to 90 degrees.If the phase difference is within some predetermined window of 90degrees, then at step 1006, the speaker drive frequency is changed sothat the next phase measurement is on the other side of 90 degrees.

At step 1007, a determination is made as to whether the last two phasemeasurements straddle 90 degrees. If not, the system is reset back tostep 1001. If so, then the last two phase measurements (and theircorresponding frequencies) are used to calculate the resonant frequency,using a linear interpolation to find the frequency at which the phasedifference is 90 degrees.

At step 1009, the temperature of the system is measured. Using the knownvariables, the relevant volume is measured using the equation(volume=k1/((f^2/T)−k2), where k1 and k2 are calibration constants(e.g., the physical geometry and molecular properties of the gas), “f”is the calculated resonant frequency, and “T” is the measuredtemperature in degrees Kelvin.

FIG. 11 is a schematic diagram of signal processing techniques accordingto an embodiment of the invention. The technique illustrated is similarto the technique displayed in FIG. 9, except that a voltage-controlledoscillator, or VCO 1106, is used instead of a processor to generatespeaker drive signals, with VCO 1106 input driven by the output from XOR1104 and then passed through integrator 1105. In principle, this circuitwill automatically find the system's resonant frequency by locking ontothe 90 degree phase difference. The integrator output is only stationarywith 50% of the XOR 1104 output duty cycle. The VCO input and output isthen altered to maintain a 50% XOR duty cycle. With this technique, anexternal processor (not shown) can either measure the input voltage toVCO 1106 (with voltage being substantially proportional to frequency),or can measure the frequency of the signal driving speaker 1107, or canmeasure the frequencies of microphones 1101 and 1102, or can measure theoutput from XOR 1104.

FIG. 12 is a flow chart of the signal processing technique illustratedin FIG. 11, according to an embodiment of the invention. In thisembodiment, at step 1201, a frequency measurement counter is configured,possibly using a high-speed timer to measure the frequency output fromthe VCO, or measured by the microphones.

At step 1202 the temperature of the system is measured. Using thisinformation, the volume is calculated using the equation(volume=k1/((f^2/T)−k2), where k1 and k2 are calibration constants(e.g., the physical geometry and molecular properties of the gas), “f”is the calculated resonant frequency, and “T” is the measuredtemperature in degrees Kelvin.

FIG. 13 is a schematic diagram of a signal processing technique using aspeaker impulse, according to an embodiment of the invention. In thisembodiment, driver 1304 applies an impulse to speaker 1305. Themicrophone output from microphone 1301 will deliver a resonant responseto processor 1303. The frequency can, in principle, be determined byeither time between the edges at the timer/counter, or by processing theanalog input stream for spectral content. This embodiment would, intheory, eliminate the reference microphone. In a related embodiment, ifthe speaker dynamics are well behaved, the reference microphone can, intheory, be eliminated; the phase difference between the microphone'soutput and the speaker drive signals can be measured instead.

FIG. 14 is a flow chart of the signal processing technique illustratedin FIG. 13. At step 1401, the frequency measurement hardware isconfigured. This can be performed using either a high-speed timer tomeasure the time differences between the microphone's zero crossing, orby using an analog to digital converter using high-frequency samplingand algorithms to examine the spectral content of the output.

At step 1402, an impulse is sent to the speaker. At step 1403, data isrecorded as the microphone's output reacts to the second-order ringingof the resonator and finishes decaying. The resonant frequency ismeasured at step 1404 using the microphone's output. The frequency isassociated with the underdamped second-order system.

The temperature is then measured at step 1405, and at step 1406, therelevant volume is then calculated using the equation(volume=k1/((f^2/T)−k2), where k1 and k2 are calibration constants(e.g., the physical geometry and molecular properties of the gas), “f”′is the calculated resonant frequency, and “T” is the measuredtemperature in degrees Kelvin.

The signal processing techniques described above can be performed usingamplitude ratios instead of resonances. This technique does notspecifically require the presence of an acoustic port, although withstandard electronics, amplitude measurements typically lack the accuracyand precision of phase measurements. With newer, higher performanceanalog to digital converters and digital signal processors, amplituderatio measurements can be an accurate substitute.

FIG. 15 is an embodiment of the invention that does not require thepresence of an acoustic port. Variable volume 1501 can be measured bydriving the speaker sinusoidally and measuring the ratio of theamplitudes at microphone 1503 and microphone 1504. Given that thespeaker is a displacement device, the pressure increase in the variablevolume will be proportional to the pressure decrease in reference volume1505. When reference volume 1505 and variable volume 1501 are equal,both microphones output the same signal level and are 180 degrees out ofphase (assuming identical microphones). If the variable volume is onehalf the size of the reference volume, the output from microphone 1504is twice that of microphone since, for the same speaker displacement,the acoustic pressure change in variable volume 1501 (as a portion ofits nominal value) is twice as large as the change in the referencevolume. The relationship is true as long as the drive frequency for thespeaker produces an acoustic wavelength much longer than any of thevolumes' dimensions.

The above amplitude ratio technique is also useful when implementing anacoustic volume sensor with an acoustic port. At frequencies much lessthan the resonances of the system, the acoustic port becomes effectivelytransparent (as in FIG. 16), and the “fixed” and “variable” volumescannot be distinguished. This embodiment can be considered alow-frequency approximation of acoustic volume sensing.

At frequencies much higher than the system resonances, the acousticport's impedance becomes significant and no acoustic energy passes fromthe port into the variable volume, as is shown in FIG. 17. At suchfrequencies, the ratio of the amplitudes between microphone 1701 and1702 is fixed, and is independent of the variable volume(ratio=reference volume/fixed volume).

FIG. 18 is a flow chart of a signal processing technique using amplituderatio measurements, according to an embodiment of the invention. In thisembodiment, at step 1801, the speaker is set into sinusoidaloscillations at a fixed frequency. If an acoustic port is present, thefrequency used can be much less than the resonant frequency of theacoustic volume sensor.

At step 1802, the amplitudes output from the two microphones aremeasured. If desired, the phase of the two outputs can be confirmed tobe 180 degrees out of phase. At step 1803, the variable volume iscalculated using the equation volume=reference volume*(referencemicrophone amplitude/front microphone amplitude).

If desired, one can cycle through multiple frequencies to confirm thevolume measurement. The measurement should be independent of frequency,the presence of air bubbles within the variable fluid volume, or other“acoustic leaks” or microphone or electronics errors that may bedetected.

If desired, using an amplitude ratio technique, a volume measurement maybe performed using a frequency much larger than the resonant frequencyof the system. The volume measurement in this case should beapproximately equal to the fixed volume and approximately independent ofthe variable volume.

The foregoing description of the embodiments of the invention has beenpresented only for the purpose of illustration and description and isnot intended to be exhaustive or to limit the invention to the preciseforms disclosed. Numerous modifications and adaptations thereof will beapparent to those skilled in the art without departing from the spiritand scope of the present invention.

What is claimed is:
 1. A method for metering fluid output comprising:providing a printed circuit board having a first microphone, a secondmicrophone and an acoustic source enclosing the printed circuit boardwith a housing in such a way as to define a first volume of an acousticsystem, the acoustic system having a resonant frequency; mounting adiaphragm covered fluid region against the housing to define an airregion between the housing and fluid region, the air region being a partof the acoustic system; fluidically coupling an output valve to thefluid region; coupling the first microphone to the first volume;coupling the acoustic source to the first volume; coupling the secondmicrophone to the air region; exciting the acoustic system at apre-determined frequency with the acoustic source; receiving a firstsignal from the first microphone associated with an acoustic response ofthe first volume to excitement at a pre-determined frequency; receivinga second signal from the second microphone associated with an acousticresponse of the air region to excitement at a pre-determined frequency;determining a volume of the air region associated with the first signaland the second signal; and controlling the output valve to meter fluidfrom the fluid region associated with the volume of the air region. 2.The method for metering fluid output of claim 1, further comprisingequalizing a pressure between the first volume and the air regionthrough a hole in the printed circuit board.
 3. The method for meteringfluid output of claim 1, wherein a second volume is defined by the airregion and fluid region.
 4. The method for metering fluid output ofclaim 1, further comprising: measuring a temperature of the acousticsystem with a temperature sensor on the printed circuit board; andfurther determining the volume of the air region associated with thetemperature of the acoustic system.
 5. The method for metering fluidoutput of claim 1, wherein the diaphragm covered fluid region is part ofa disposable drug cassette.
 6. The method for metering fluid output ofclaim 1, further comprising: exciting the acoustic system at a pluralityof pre-determined frequencies; receiving a plurality of signal pairs, asignal pair being a pair of signals from the first and secondmicrophones associated with the acoustic response of the first volumeand air region respectively to excitement at a single pre-determinedfrequency; and further determining the volume of the air regionassociated with the plurality of signal pairs.
 7. The method of claim 1,further comprising determining a gain of the second signal relative tothe first signal; determining a phase shift of the second signalrelative to the first signal; and further determining a volume of theair region associated with the gain and phase shift of the second signalrelative to the first signal.
 8. A method for metering fluid outputcomprising: providing a printed circuit board having a first microphone,a second microphone and an acoustic source enclosing the printed circuitboard with a housing in such a way as to define a first volume of anacoustic system, the acoustic system having a resonant frequency;mounting a diaphragm covered fluid region against the housing to definea second volume, the second volume includes a gas region and a fluidregion, the second volume being part of the acoustic system, the fluidregion having an output; fluidically coupling an input valve to thefluid region; coupling the first microphone to the first volume;coupling the acoustic source to the first volume; coupling the secondmicrophone to the second volume; exciting the acoustic system at apre-determined frequency with the acoustic source; receiving a firstsignal from the first microphone associated with an acoustic response ofthe first volume to excitement at a pre-determined frequency; receivinga second signal from the second microphone associated with an acousticresponse of the second volume to excitement at a pre-determinedfrequency; determining a volume of the air region associated with thefirst signal and the second signal; and allowing fluid to enter thefluid region for metering upon output associated with the volume of theair region.
 9. The method for metering fluid output of claim 8, furthercomprising equalizing a pressure between the first volume and the airregion through a hole in the printed circuit board.
 10. The method formetering fluid output of claim 8, further comprising: measuring thetemperature of a acoustic system with a temperature sensor on theprinted circuit board; and further determining the volume of the airregion associated with the temperature of the acoustic system.
 11. Themethod for metering fluid output of claim 8, wherein the diaphragmcovered fluid region is part of a disposable drug cassette.
 12. Themethod for metering fluid output of claim 8, further comprising:exciting the acoustic system at a plurality of pre-determinedfrequencies; receiving a plurality of signal pairs, a signal pair beinga pair of signals from the first and second microphones associated withan acoustic response of the first volume and air region respectively toexcitement at a single pre-determined frequency; and further determiningthe volume of the air region associated with the plurality of signalpairs.
 13. The method for metering fluid output of claim 8, furthercomprising determining a gain of the second signal relative to the firstsignal; determining a phase shift of the second signal relative to thefirst signal; and further determining the volume of the air regionassociated with the gain and phase shift of the second signal relativeto the first signal.
 14. A method for outputting fluid comprising:providing a printed circuit board having a first microphone, a secondmicrophone and an acoustic source enclosing the printed circuit boardwith a housing in such a way as to define a reference volume of anacoustic system, the acoustic system having a resonant frequency;mounting a diaphragm covered fluid region against the housing to definea variable volume, the variable volume being part of the acousticsystem, the fluid region having an output; fluidically coupling a valveto the fluid region; coupling the first microphone to the referencevolume; coupling the acoustic source to the reference volume; couplingthe second microphone to the variable volume; exciting the acousticsystem at a pre-determined frequency with the acoustic source; receivinga first signal from the first microphone associated with an acousticresponse of the reference volume to excitement at a pre-determinedfrequency; receiving a second signal from the second microphoneassociated with an acoustic response of the variable volume toexcitement at a pre-determined frequency; determining the resonantfrequency of the acoustic system; determining a volume of the variablevolume associated with the resonant frequency; and controlling the valveto allow an amount of fluid to exit the fluid region, the amount offluid being associated with the determined volume of the variablevolume.
 15. The method for outputting fluid of claim 14, furthercomprising equalizing a pressure between the reference volume and thevariable volume through a hole in the printed circuit board.
 16. Themethod for outputting fluid of claim 14, further comprising: measuring atemperature of the acoustic system with a temperature sensor on theprinted circuit board; and further determining the volume of thevariable volume associated with the temperature of the acoustic system.17. The method for outputting fluid of claim 14, wherein the diaphragmcovered fluid region is part of a disposable drug cassette.
 18. Themethod for outputting fluid of claim 14, further comprising: excitingthe acoustic system at a plurality of pre-determined frequencies;receiving a plurality of signal pairs, a signal pair being a pair ofsignals from the first and second microphones associated with theacoustic response of the reference volume and variable volumerespectively to excitement at a single pre-determined frequency; andfurther determining the resonant frequency of the acoustic systemassociated with the plurality of signal pairs.
 19. The method foroutputting fluid of claim 14, further comprising determining a gain ofthe second signal relative to the first signal; determining a phaseshift of the second signal relative to the first signal; and furtherdetermining the resonant frequency of the acoustic system associatedwith the gain and phase shift of the second signal relative to the firstsignal.
 20. The method for outputting fluid of claim 14, furthercomprising modeling the acoustic system as a second order system model;and further determining a resonant frequency of the acoustic systemassociated with the second order system model.
 21. The method foroutputting fluid of claim 14, further comprising modeling the acousticsystem with an electrical analog model; and further determining aresonant frequency of the acoustic system associated with the electricalanalog model.
 22. The method for outputting fluid of claim 14, furthercomprising modeling the acoustic system with a mechanical analog model;and further determining a resonant frequency of the acoustic systemassociated with the mechanical analog model.
 23. The method foroutputting fluid comprising: enclosing a printed circuit board within ahousing, the printed circuit board including a speaker and a microphone;defining a volume within the housing, the volume including an air regionand a fluid region, the fluid region having a fluid output; fluidicallyconnecting a valve to the fluid region; coupling the microphone to thevolume; coupling the acoustic source to the volume; exciting the airregion at a pre-determined frequency with the acoustic source; receivinga signal from the microphone associated with an acoustic response of theair region to excitement at a pre-determined frequency; determining avolume of the air region associated with the signal; and controlling thevalve to allow an amount of fluid to exit the fluid region, the amountof fluid being associated with the determined volume of the air region.24. The method for outputting fluid of claim 23, further comprising:measuring a temperature of the air region with a temperature sensor onthe printed circuit board; and further determining the volume of the airregion associated with the temperature of the acoustic system.